A small molecule inhibitor of Pim protein kinases blocks the growth of precursor T-cell lymphoblastic leukemia/lymphoma

Ying Wei Lin, Zanna M. Beharry, Elizabeth G. Hill, Jin H. Song, Wenxue Wang, Zuping Xia, Zhenhua Zhang, Peter D. Aplan, Jon C. Aster, Charles Smith, Andrew S. Kraft

Research output: Contribution to journalArticle

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Abstract

The serine/threonine Pim kinases are upregulated in specific hematologic neoplasms, and play an important role in key signal transduction pathways, including those regulated by MYC, MYCN, FLT3-ITD, BCR-ABL, HOXA9, and EWS fusions. We demonstrate that SMI-4a, a novel benzylidene-thiazolidine-2, 4-dione small molecule inhibitor of the Pim kinases, kills a wide range of both myeloid and lymphoid cell lines with precursor T-cell lymphoblastic leukemia/lymphoma (pre - T-LBL/T-ALL) being highly sensitive. Incubation of pre - T-LBL cells with SMI-4a induced G1 phase cell-cycle arrest secondary to a dose-dependent induction of p27Kip1, apoptosis through the mitochondrial pathway, and inhibition of the mammalian target of rapamycin C1 (mTORC1) pathway based on decreases in phosphop70 S6K and phospho-4E-BP1, 2 substrates of this enzyme. In addition, treatment of these cells with SMI-4a was found to induce phosphorylation of extracellular signal-related kinase1/2 (ERK1/2), and the combination of SMI-4a and a mitogenactivated protein kinase kinase 1/2 (MEK1/2) inhibitor was highly synergistic in killing pre - T-LBL cells. In immunodeficient mice carrying subcutaneous pre - T-LBL tumors, treatment twice daily with SMI-4a caused a significant delay in the tumor growth without any change in the weight, blood counts, or chemistries. Our data suggest that inhibition of the Pim protein kinases may be developed as a therapeutic strategy for the treatment of pre - T-LBL.

Original languageEnglish (US)
Pages (from-to)824-833
Number of pages10
JournalBlood
Volume115
Issue number4
DOIs
StatePublished - Jan 28 2010

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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
T-cells
Protein Kinases
Cells
Molecules
Tumors
Growth
G1 Phase Cell Cycle Checkpoints
Signal transduction
Phosphorylation
Proteins
Protein-Serine-Threonine Kinases
G1 Phase
Hematologic Neoplasms
Myeloid Cells
Sirolimus
Threonine
Serine
Signal Transduction
Neoplasms

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Lin, Y. W., Beharry, Z. M., Hill, E. G., Song, J. H., Wang, W., Xia, Z., ... Kraft, A. S. (2010). A small molecule inhibitor of Pim protein kinases blocks the growth of precursor T-cell lymphoblastic leukemia/lymphoma. Blood, 115(4), 824-833. https://doi.org/10.1182/blood-2009-07-233445
Lin, Ying Wei ; Beharry, Zanna M. ; Hill, Elizabeth G. ; Song, Jin H. ; Wang, Wenxue ; Xia, Zuping ; Zhang, Zhenhua ; Aplan, Peter D. ; Aster, Jon C. ; Smith, Charles ; Kraft, Andrew S. / A small molecule inhibitor of Pim protein kinases blocks the growth of precursor T-cell lymphoblastic leukemia/lymphoma. In: Blood. 2010 ; Vol. 115, No. 4. pp. 824-833.
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abstract = "The serine/threonine Pim kinases are upregulated in specific hematologic neoplasms, and play an important role in key signal transduction pathways, including those regulated by MYC, MYCN, FLT3-ITD, BCR-ABL, HOXA9, and EWS fusions. We demonstrate that SMI-4a, a novel benzylidene-thiazolidine-2, 4-dione small molecule inhibitor of the Pim kinases, kills a wide range of both myeloid and lymphoid cell lines with precursor T-cell lymphoblastic leukemia/lymphoma (pre - T-LBL/T-ALL) being highly sensitive. Incubation of pre - T-LBL cells with SMI-4a induced G1 phase cell-cycle arrest secondary to a dose-dependent induction of p27Kip1, apoptosis through the mitochondrial pathway, and inhibition of the mammalian target of rapamycin C1 (mTORC1) pathway based on decreases in phosphop70 S6K and phospho-4E-BP1, 2 substrates of this enzyme. In addition, treatment of these cells with SMI-4a was found to induce phosphorylation of extracellular signal-related kinase1/2 (ERK1/2), and the combination of SMI-4a and a mitogenactivated protein kinase kinase 1/2 (MEK1/2) inhibitor was highly synergistic in killing pre - T-LBL cells. In immunodeficient mice carrying subcutaneous pre - T-LBL tumors, treatment twice daily with SMI-4a caused a significant delay in the tumor growth without any change in the weight, blood counts, or chemistries. Our data suggest that inhibition of the Pim protein kinases may be developed as a therapeutic strategy for the treatment of pre - T-LBL.",
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Lin, YW, Beharry, ZM, Hill, EG, Song, JH, Wang, W, Xia, Z, Zhang, Z, Aplan, PD, Aster, JC, Smith, C & Kraft, AS 2010, 'A small molecule inhibitor of Pim protein kinases blocks the growth of precursor T-cell lymphoblastic leukemia/lymphoma', Blood, vol. 115, no. 4, pp. 824-833. https://doi.org/10.1182/blood-2009-07-233445

A small molecule inhibitor of Pim protein kinases blocks the growth of precursor T-cell lymphoblastic leukemia/lymphoma. / Lin, Ying Wei; Beharry, Zanna M.; Hill, Elizabeth G.; Song, Jin H.; Wang, Wenxue; Xia, Zuping; Zhang, Zhenhua; Aplan, Peter D.; Aster, Jon C.; Smith, Charles; Kraft, Andrew S.

In: Blood, Vol. 115, No. 4, 28.01.2010, p. 824-833.

Research output: Contribution to journalArticle

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T1 - A small molecule inhibitor of Pim protein kinases blocks the growth of precursor T-cell lymphoblastic leukemia/lymphoma

AU - Lin, Ying Wei

AU - Beharry, Zanna M.

AU - Hill, Elizabeth G.

AU - Song, Jin H.

AU - Wang, Wenxue

AU - Xia, Zuping

AU - Zhang, Zhenhua

AU - Aplan, Peter D.

AU - Aster, Jon C.

AU - Smith, Charles

AU - Kraft, Andrew S.

PY - 2010/1/28

Y1 - 2010/1/28

N2 - The serine/threonine Pim kinases are upregulated in specific hematologic neoplasms, and play an important role in key signal transduction pathways, including those regulated by MYC, MYCN, FLT3-ITD, BCR-ABL, HOXA9, and EWS fusions. We demonstrate that SMI-4a, a novel benzylidene-thiazolidine-2, 4-dione small molecule inhibitor of the Pim kinases, kills a wide range of both myeloid and lymphoid cell lines with precursor T-cell lymphoblastic leukemia/lymphoma (pre - T-LBL/T-ALL) being highly sensitive. Incubation of pre - T-LBL cells with SMI-4a induced G1 phase cell-cycle arrest secondary to a dose-dependent induction of p27Kip1, apoptosis through the mitochondrial pathway, and inhibition of the mammalian target of rapamycin C1 (mTORC1) pathway based on decreases in phosphop70 S6K and phospho-4E-BP1, 2 substrates of this enzyme. In addition, treatment of these cells with SMI-4a was found to induce phosphorylation of extracellular signal-related kinase1/2 (ERK1/2), and the combination of SMI-4a and a mitogenactivated protein kinase kinase 1/2 (MEK1/2) inhibitor was highly synergistic in killing pre - T-LBL cells. In immunodeficient mice carrying subcutaneous pre - T-LBL tumors, treatment twice daily with SMI-4a caused a significant delay in the tumor growth without any change in the weight, blood counts, or chemistries. Our data suggest that inhibition of the Pim protein kinases may be developed as a therapeutic strategy for the treatment of pre - T-LBL.

AB - The serine/threonine Pim kinases are upregulated in specific hematologic neoplasms, and play an important role in key signal transduction pathways, including those regulated by MYC, MYCN, FLT3-ITD, BCR-ABL, HOXA9, and EWS fusions. We demonstrate that SMI-4a, a novel benzylidene-thiazolidine-2, 4-dione small molecule inhibitor of the Pim kinases, kills a wide range of both myeloid and lymphoid cell lines with precursor T-cell lymphoblastic leukemia/lymphoma (pre - T-LBL/T-ALL) being highly sensitive. Incubation of pre - T-LBL cells with SMI-4a induced G1 phase cell-cycle arrest secondary to a dose-dependent induction of p27Kip1, apoptosis through the mitochondrial pathway, and inhibition of the mammalian target of rapamycin C1 (mTORC1) pathway based on decreases in phosphop70 S6K and phospho-4E-BP1, 2 substrates of this enzyme. In addition, treatment of these cells with SMI-4a was found to induce phosphorylation of extracellular signal-related kinase1/2 (ERK1/2), and the combination of SMI-4a and a mitogenactivated protein kinase kinase 1/2 (MEK1/2) inhibitor was highly synergistic in killing pre - T-LBL cells. In immunodeficient mice carrying subcutaneous pre - T-LBL tumors, treatment twice daily with SMI-4a caused a significant delay in the tumor growth without any change in the weight, blood counts, or chemistries. Our data suggest that inhibition of the Pim protein kinases may be developed as a therapeutic strategy for the treatment of pre - T-LBL.

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